Oxidative stress modulates theophylline effects on steroid responsiveness.
Oxidative stress is a central factor in many chronic inflammatory diseases such as severe asthma and chronic obstructive pulmonary disease (COPD). Oxidative stress reduces the anti-inflammatory corticosteroid action and may therefore contribute to the relative corticosteroid insensitivity seen in these diseases. Low concentrations of theophylline can restore the anti-inflammatory action of corticosteroids in oxidant exposed cells, however the mechanism remains unknown. Here, we demonstrate that a low concentration of theophylline restores corticosteroid repression of pro-inflammatory mediator release and histone acetylation in oxidant exposed cells. Global gene expression analysis shows that theophylline regulates distinct pathways in naïve and oxidant exposed cells and reverses oxidant mediated modulated of pathways. Furthermore, quantitative chemoproteomics revealed that theophylline has few high affinity targets in naive cells but an elevated affinity in oxidant stressed cells. In conclusion, oxidative stress alters theophylline binding profile and gene expression which may result in restoration of corticosteroid function.
Marwick
John A
JA
National Heart & Lung Institute, Airways Disease Section, Imperial College London, Guy-Scadding Building, Dovehouse Steet, London SW3 6LY, UK. j.marwick@imperial.ac.uk
Wallis
Gillian
G
Meja
Koremu
K
Kuster
Bernhard
B
Bouwmeester
Tewis
T
Chakravarty
Probir
P
Fletcher
Danielle
D
Whittaker
Paul A
PA
Barnes
Peter J
PJ
Ito
Kazuhiro
K
Adcock
Ian M
IM
Kirkham
Paul A
PA
D000107:Acetylation; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D040901:Proteomics; D013806:Theophylline / Q000494:pharmacology*
D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D001993:Bronchodilator Agents; D006657:Histones; D016877:Oxidants; D010726:Phosphodiesterase Inhibitors; D003907:Dexamethasone; D013806:Theophylline